Diabetes is rapidly becoming a major global health crisis in the 21st century. There are currently 537 million persons between the ages of 20 and 79 who are living with diabetes, which is equal to 10% of the world’s population [1]. It is predicted that the number of individuals with diabetes will increase to 643 million by 2030, and further to 783 million by 2045 [2]. Diabetes is responsible for the majority of neuronal damage, visual impairment, and kidney failure in the non-elderly population. Approximately half of diabetic peripheral neuropathies (DPNs) may not exhibit symptoms, underscoring the importance of comprehensive screening, as neglecting foot care measures heightens the likelihood of harm.
Diabetic neuropathy, a condition characterized by high prevalence and disability, poses significant challenges in terms of management. These challenges include various complications, which not only burden individuals but also incur substantial financial costs. Diabetic foot is a significant factor in the global burden of disability and decreased quality of life. 14 -24% of diabetic foot patients require major or minor lower limb amputations [3]. There are 70 million diabetics in India out of which 50% have diabetic peripheral neuropathy and nearly 25-34% of them develop diabetic foot ulcer (DFU) and 1.2 million need special care for DFU [4]. The 5-year survival rate of diabetic foot patients with major amputations is 30%. There are 100000 registered amputations per year due to diabetes in India [5].
Additionally, individuals with a prediabetic status are more likely to develop DN at an earlier stage. The main complication associated with peripheral sensory neuropathy is the development of DFUs and subsequent minor or major amputations. Research has indicated that having underlying peripheral neuropathy raises the risk of any amputation by 1.7 times [6]. The risk increases by a factor of 12 if there is a deformity (caused by motor neuropathy) and increases significantly to 36 times if there is a previous history of ulcers.
Classifications of DPN
The primary categories of neurologic disorders in DM encompass:
- Subclinical neuropathy is determined by abnormalities in electrodiagnostic and quantitative sensory testing
- Diffuse clinical neuropathy with distal symmetric sensorimotor and autonomic syndromes.
- Sensory or sensorimotor polyneuropathy
- Selective small-fibre polyneuropathy
- Autonomic neuropathy
- Focal syndromes:
- Truncal mononeuropathy
- Mononeuritis multiplex
- Asymmetric lower limb motor neuropathy (amyotrophy)
- Cranial neuropathy
- Mixed forms
Subclinical neuropathy is identified when there are no clinical indications of neuropathy, but abnormal electrodiagnostic tests show reduced nerve conduction velocity (NCV) or amplitude; quantitative sensory tests (QSTS) reveal altered perception of vibration, touch, and temperature; and autonomic function tests (AFTs) indicate dysfunction in sympathetic and parasympathetic nerves.
Risk factors for peripheral neuropathy
The risk factors for the development of diabetes-related peripheral neuropathy are as follows:
The risk factors with a major impact are:
- Poor control of blood sugar levels
- Long-standing diabetes
- Damage to blood vessels
- Alcohol consumption
- Metformin use
The risk factors with a minor impact are:
- Autoimmune factors
- Genetic susceptibility
- Smoking
- Low levels of high-density lipoprotein (HDL)
- Cardiovascular disease
A study found that the duration of diabetes mellitus (DM) is a major risk factor for neuropathy. Patients with DM for more than 15 years have an odds ratio of 8.03 (95% confidence interval 5.96-10.8, p<0.001) for developing neuropathy compared to those with a duration of less than 5 years [7]. The study also found that increasing age, the presence of dyslipidemia, and the presence of other microvascular complications are significantly associated with peripheral neuropathy (Fig.1).
Pathogenesis of peripheral neuropathy
The pathophysiology of diabetic peripheral neuropathy is multifactorial and is thought to result from vascular disease occluding the vasa nervorum; endothelial and myelin synthesis dysfunction and diminishing sodium-potassium adenine triphosphatase (ATPase) activity; chronic hyperosmolarity, causing oedema of nerve trunks; and effects of increased sorbitol and fructose.
Nonenzymatic glycation predisposes ligaments to stiffness. Neuropathy causes loss of protective sensation and loss of coordination of muscle groups in the foot and leg, both of which increase mechanical stresses during ambulation.
Motor dysfunction of peripheral nerves in diabetic neuropathy leads to muscular imbalances in the diabetic foot. Muscle wasting of the intrinsic pedal muscles leads to overpowering of the spared extrinsic muscles, which results in significant forefoot deformities such as claw toes or hammer toes. Autonomic dysfunction of the peripheral nervous system may lead to sudomotor dysfunction. This will result in dry, cracked skin, and intrinsic minus foot, which is more prone to injury and breakdown.
The result of loss of sensation in the foot is repetitive stress; unnoticed injuries and fractures; structural foot deformity, such as hammertoes, bunions, metatarsal deformities, or Charcot foot; further stress; and eventual tissue breakdown.
Unnoticed excessive heat or cold, pressure from a poorly fitting shoe, or damage from a blunt or sharp object inadvertently left in the shoe may cause blistering and ulceration. These factors, combined with poor arterial inflow, confer a high risk of limb loss on the patient with diabetes.
Metabolic Hypothesis
Chronic hyperglycemia cause damage to peripheral nerves through various pathways, one of which involves an increase in the entry of polyol that is regulated by aldose reductase, also known as the polyol pathway. Another theory suggests that injury to the endoneurium of peripheral nerves is caused by an excessive build-up of advanced glycation end-products (AGES). Additionally, hyperglycemia contributes to peripheral neuropathy by generating oxidative stress-induced free radicals during the glycolytic process ( Fig.2 and 3).
Immune Hypothesis
In patients with DN, the presence of antiphospholipid antibodies and autoantibodies to gangliosides indicates a potential role of these factors in the development of DN.
Microvascular Hypothesis
Nerve ischemia is caused by microvascular insufficiency resulting from inadequate blood supply to the vasa vasorum. This insufficiency is contributed by an increase in the thickness of the vessel walls, hyalinization of the basal lamina, and impaired vasoconstriction and vasodilation.
Neurotrophic Hypothesis
Patients with DN exhibit a deficiency in neurotrophic factors such as nerve growth factor (NGF), neurotrophin-3/4/5, and insulin-like growth factor (IGF)-1
Clinical evaluation
The neuropathic symptoms are divided into focal and diffuse forms, of which the latter is far more common .
Diffuse Neuropathies
One should look for specific motor and sensory symptoms in patients as it helps in understanding the underlying nerves at fault. This can be understood from the following:
Acute Painful Neuropathy
Some patients with diabetes mellitus (DM) present with acute symptoms that persist for less than six months and are accompanied by moderate-to-severe pain. The pain caused by sensory neuropathy worsens at night and is often more pronounced in the feet than in the hands. As a result of the nocturnal pain, patients frequently complain of sleep disturbances and insomnia. The nature of the pain can be described as burning, stabbing, tingling, pins and needles, paresthesia, or a prick sensation.
In this scenario, the following possibilities should be considered:
– Insulin neuritis – Rapid correction of blood glucose levels – Chronic alcohol consumption – Associated amyloidosis and multiple myeloma – Human immunodeficiency virus (HIV) infection – Heavy metal poisoning (e.g., arsenic) – Fabry’s disease
Chronic Painful Neuropathy
Chronic painful neuropathy is a separate condition that typically develops later in individuals who have been diagnosed with DM for several years. In this case, the debilitating pain persists for more than six months.
Over time, many patients may experience a lack of pain, which is not necessarily indicative of symptom improvement, but rather due to neuronal loss. Hyperalgesia, on the other hand, refers to an increased perception of pain even in response to normal stimuli. Allodynia is the sensation of pain caused by a stimulus that is not typically painful.
The sensation of burning and pricking is attributed to C and Ao fibers, while Aẞ fibers are responsible for dysesthesias, paresthesias, and allodynia.
Large-fiber neuropathies
Large-fiber neuropathies affect the sensory or motor nerves. These neuropathies display more signs than symptoms. Fiber neuropathies cause changes in vibration perception, position sense, and cold thermal perception. These myelinated, rapidly conducting fibers primarily affect the toes rather than the fingers, as they are length-dependent fibres that are more noticeable in electromyography (EMG). The alteration of these fibres leads to a sensation of walking on cotton in the feet and, in severe cases, difficulty in distinguishing shapes and turning pages in books.
The clinical presentation of large-fiber neuropathies includes:
- Impaired vibration perception (often the first objective evidence) and position sense
- Decreased tendon reflexes.
- A deep-seated gnawing pain similar to a toothache in the bones of the feet, or even a crushing or cramp-like pain
- Wasting of the small muscles in the feet, resulting in hammer toes.
- Shortening of the Achilles tendon, leading to pes equinus.
- Increased blood flow, causing warm foot
Proximal motor neuropathies
Proximal motor neuropathies, also known as femoral neuropathy, diabetic amyotrophy, and diabetic neuropathic cachexia, have distinct symptoms and signs. This condition primarily affects the elderly, typically occurring after the age of fifty. The onset of symptoms can be gradual or abrupt, beginning in one leg and progressing to the other. The initial symptom is often pain in the thighs, hips, or buttocks, followed by proximal myopathy. Interestingly, heel or toe standing is usually unaffected despite weakness in the proximal muscles. Patients may experience spontaneous or provoked fasciculations, and electromyography (EMG) often reveals features of lumbosacral plexopathy. While proximal motor neuropathy is commonly associated with diabetes mellitus, it is important to consider other potential causes such as chronic inflammatory demyelinating polyneuropathy (CIDP), monoclonal gammopathy of unknown significance (MGUS), circulating GMI antibodies, and antibodies to neuronal cells and inflammatory vasculitis. If demyelination is the predominant finding on EMG, further investigation into causes other than diabetes mellitus is warranted, as the treatment options may differ in cases of femoral neuropathy.
Asymmetric neuropathies
Mononeuropathy
- Generally acute with pain.
- Usually in older population.
- It can involve truncal and cranial nerves (III and VI).
- Self-limiting and resolving in 6-8 weeks.
- Usually due to vessel occlusion.
- Treatment: Symptomatic for pain and physiotherapy.
Entrapment neuropathy
- Starts slowly and progresses slowly.
- Commonly involves the median (carpal tunnel), ulnar, radial, femoral, and lateral cutaneous nerve of the thigh.
- Treated with splints, nonsteroidal anti-inflammatory drugs (NSAIDs), and local injection.
- In some cases, surgery to decompress.
Mononeuropathies must be distinguished from entrapment syndromes, which start slowly, progress, and persist without intervention.
Nerve conduction studies
Electromyography-nerve conduction velocity (EMG-NCV) has become a crucial technique for tracking the early development and progression of peripheral neuropathy. These measures are objective, quantitative, noninvasive, and highly sensitive. The primary purpose of EMG is to distinguish between diabetic neuropathy and neuropathy of non-diabetic origin. Studies have rep that patients with an average HbA1c level >10% over an 8-year period exhibited a significant decrease in NCV.
Newer techniques
Newer techniques for evaluating small-fibre function include the use of:
- Corneal confocal microscopy, which allows the identification of unmyelinated axons in the cornea.
- Sudomotor function devices.
Treatment
Small fiber neuropathy
In order to manage the condition, it is important to engage in certain practices. For example, daily inspection of the feet is necessary, and using a handheld mirror to examine the soles of the feet can be helpful. It is also crucial to wear well-fitting Microcellular rubber (MCR) shoes to ensure comfort and prevent further complications. Additionally, it is advised to avoid exposing the feet to extreme temperatures. To combat skin drying and cracking, the use of moisturizing creams is recommended. After bathing, it is essential to thoroughly dry the feet. When it comes to nail care, cutting them transversely is the recommended approach.
Large Fiber Neuropathy
In patients with DM and large fiber neuropathy, it is important to focus on gait and strength training. This is because individuals with this condition have an increased risk of falls due to sensory ataxia, weakness, incoordination, muscle wasting, and the possibility of fractures following falls. This is particularly true for post-menopausal women. Therefore, enhancing muscle strength is crucial in order to prevent complications related to DM and small fiber neuropathy. Microcellular rubber (MCR) footwear is the most commonly used material for patients with DM and peripheral neuropathy. It is recommended to use footwear with a shore value between 8 and 15 for those with DM. MCR footwear has proven to be effective in preventing the development and recurrence of ulcers.
Pharmacological treatment
Many prescription medications are available for diabetes-related nerve pain. Pain-relieving prescription treatments may include:
Anti-seizure drugs. Some medications used to treat seizure disorders (epilepsy) are also used to ease nerve pain. The ADA recommends starting with pregabalin (Lyrica). Gabapentin (Gralise, Neurontin) also is an option. Side effects may include drowsiness, dizziness, and swelling in the hands and feet [8].
Antidepressants. Some antidepressants ease nerve pain [8]. Tricyclic antidepressants may help with mild to moderate nerve pain. Drugs in this class include amitriptyline, nortriptyline (Pamelor) and desipramine (Norpramin). Side effects can be bothersome and include dry mouth, constipation, drowsiness and difficulty concentrating. These medications may also cause dizziness when changing position, such as from lying down to standing (orthostatic hypotension). Serotonin and norepinephrine reuptake inhibitors (SNRIs) are another type of antidepressant that may help with nerve pain and have fewer side effects. The ADA recommends duloxetine (Cymbalta, Drizalma Sprinkle) as a first treatment. Another drug that may be used is venlafaxine (Effexor XR). Possible side effects include nausea, sleepiness, dizziness, decreased appetite and constipation. Sometimes, an antidepressant may be combined with an anti-seizure drug. These drugs can also be used with pain-relieving medication, such as medication available without a prescription. For example, one may find relief from acetaminophen (Tylenol, others) or ibuprofen (Advil, Motrin IB, others) or a skin patch with lidocaine (a numbing substance).
Conclusion
Diabetic peripheral neuropathy is a multifaceted complication of diabetes that involves intricate pathological processes and interactions between various cellular and molecular factors. An in-depth understanding of the underlying pathophysiology is crucial for physicians, enabling them to adopt a targeted approach in diagnosing, treating, and managing DPN effectively. By addressing the pathogenic mechanisms discussed above, healthcare professionals can work towards developing novel therapeutic interventions and significantly improve patient outcomes in DPN management.
Author: Dr. Sanjay Sharma, MS, Diabetic Foot Surgeon
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